Antipsychotic treatment-emergent extrapyramidal symptoms (EPS) are frequent and serious acute adverse reactions of antipsychotic drugs, the signs of which may develop within few days of starting medication. EPS is a complex phenotype that includes several recognized syndromes namely parkinsonism, akathisia, acute dystonia and dyskinesia. While the situation has improved since the pre-clozapine era, the EPS problem has by no means gone away; for example, in CATIE (Comparative Effectiveness of Antipsychotic Medications in Patients with Schizophrenia), a large effectiveness trial, 10.5% of patients stopped their assigned medication for EPS-related reasons.
Even though the exact mechanism underlying EPS is not clear, striatal dopamine D2 receptor (DRD2) blockade is believed to be the principal cause. The essential control of motor activity is assumed by the basal ganglia, whose main constituent is the striatum. In the dorsal striatum, dopamine regulates the motor activity by whether interacting with dopamine D1 receptor (DRD1) or DRD2, resulting in two different projecting pathways (“direct and “indirect” pathways) and most importantly in opposite stimulation of the thalamus. According to this model, dopamine promotes motor activity by increasing the activity of the direct pathway and, concomitantly by inhibiting the indirect pathway.
Several studies have tried to identify potential risk factors for developing EPS, such as younger age, male gender and psychiatric diagnosis, especially mood disorders. Pharmacogenetics markers have been also tested (Zhang and Malhotra, 2011, Expert Opin Drug Metab Toxicol 7:9-37). Although some genetic variant may have significant effects on EPS appearance (Gassó et al., 2009, Pharmacogenomics J 9:404-10; Greenbaum et al., 2009, Pharmacogenomics J 9:103-10) no single factor can predict this phenomenon.
Almoguera et al. [2012, Pharmacogenomics J. doi: 10.1038/tpj.2011.57 (Epub ahead of print Jan. 3, 2012)] describes the association of genetic variants in several genes with adverse effects caused by risperidone in patients with schizophrenia. All analyzed gene variants had been previously described in relation to the ability to predict patient response to risperidone or adverse effects. Almoguera et al. further disclose that ADRB2 gene variants 16Gly, SLC6A4 L/S, SLC6A4 S/S and DRD3 9Gly correlate with the onset of sexual adverse events, somnolence, EPS and weight gain in patients treated with risperidone.
WO 2011/148379 describes genotypes associated with resistance to parkinsonism and other antipsychotic-induced EPS, in particular the rs12678719 SNP in gene ZFPM2 and the rs4606 SNP in gene RGS2.
WO 2007/144874 describes genotypes associated with resistance to EPS induced by antipsychotics, especially the rs2179652, rs1933695, rs2746073, rs4606, rs1819741 and rs1152746 SNPs. Furthermore, this document identifies genotypes associated with a predisposition to the onset or aggravation of EPS. Gene variants associated with EPS are in RGS2 gene.
Xu et al. (2007, J. Clin. Psychiatry, 68:1358-67) describes the identification of the rs3803300 SNP in gene AKT1 and of a haplotype consisting of 5 SNPs in said gene that are associated with the onset of schizophrenia. However, neither the rs3803300 SNP nor the haplotype show any relationship with the onset of EPS.
Thus, there is still a need in the art for a method that allows to predict the onset EPS induced by an antipsychotic-based treatment.